Project Summary Early in Human Immunodeficieny Virus (HIV) infection, host cell proteins bind the HIV capsid during its journey from the site of entry to the nucleus. Some host cell proteins are cofactors needed to enhance HIV infection, while others have evolved to restrict HIV infection. To perform these myriad functions, host cell proteins share some common features, namely, they are oligomeric, they bind assembled capsid interfaces, or both. These shared properties serve to allow a host factor to preferably bind intact capsid cores and avoid unassembled capsid proteins that are not relevant for infection. To date, interactions between host cell proteins and assembled capsid have been difficult to study in vitro due to the lack of soluble, assembled capsid preparations. Therefore, the development of a repertoire of soluble capsid assemblies will aid in characterization of capsid-host factor interactions. The following aims will address the development and use of this new tool: Aim 1: Produce a soluble HIV-1 capsid lattice to study capsid structure and host-viral interactions. Aim 2: Biochemical and structural studies of TRIM5-capsid interactions These tools will be used to obtain high-resolution structural information on intra-capsid and TRIM5-capsid interactions, which will enable novel therapeutic avenues for HIV infection.